-
REVIEWpublished: 07 August 2015
doi: 10.3389/fimmu.2015.00387
Edited by:Heidi Noels,
RWTH Aachen University, GermanyJürgen Bernhagen,
RWTH Aachen University, Germany
Reviewed by:Rafael Franco,
University of Barcelona, SpainCatherine Anne Abbott,
Flinders University, AustraliaMark Gorrell,
University of Sydney, Australia
*Correspondence:Ingrid De Meester,
Laboratory of Medical Biochemistry,Department of
Pharmaceutical
Sciences, University of Antwerp,Universiteitsplein 1,
Antwerp 2610, [email protected]
Specialty section:This article was submitted to
Chemoattractants, a section of thejournal Frontiers in
Immunology
Received: 21 April 2015Accepted: 13 July 2015
Published: 07 August 2015
Citation:Waumans Y, Baerts L, Kehoe K,Lambeir A-M and De Meester
I(2015) The dipeptidyl peptidasefamily, prolyl oligopeptidase,
andprolyl carboxypeptidase in the
immune system and inflammatorydisease, including
atherosclerosis.
Front. Immunol. 6:387.doi: 10.3389/fimmu.2015.00387
The dipeptidyl peptidase family,prolyl oligopeptidase, and
prolylcarboxypeptidase in the immunesystem and inflammatory
disease,including atherosclerosisYannick Waumans, Lesley Baerts,
Kaat Kehoe, Anne-Marie Lambeir andIngrid De Meester*
Laboratory of Medical Biochemistry, Department of Pharmaceutical
Sciences, University of Antwerp, Antwerp, Belgium
Research from over the past 20 years has implicated dipeptidyl
peptidase (DPP) IV andits family members in many processes and
different pathologies of the immune system.Most research has been
focused on either DPPIV or just a few of its family members. It
is,however, essential to consider the entire DPP family when
discussing any one of its mem-bers. There is a substantial overlap
between family members in their substrate specificity,inhibitors,
and functions. In this review, we provide a comprehensive
discussion on therole of prolyl-specific peptidases DPPIV, FAP,
DPP8, DPP9, dipeptidyl peptidase II, prolylcarboxypeptidase, and
prolyl oligopeptidase in the immune system and its diseases.
Wehighlight possible therapeutic targets for the prevention and
treatment of atherosclerosis,a condition that lies at the frontier
between inflammation and cardiovascular disease.
Keywords: dipeptidyl peptidase, prolyl oligopeptidase,
fibroblast activation protein ααα, prolyl
carboxypeptidase,inflammation, immunophysiology,
atherosclerosis
Introduction
Research from over the past 20 years has implicated the
dipeptidyl peptidase (DPP) family in variousphysiological processes
and pathologies of the immune system.Usually only four
prolyl-specific pep-tidases are considered: DPPIV (EC 3.4.14.5),
fibroblast activation protein α (FAP; EC 3.4.21.B28),and the more
recently discovered DPP8 and DPP9 (EC 3.4.14). However, due to
similarities insubstrate specificity and structural homology, it is
more relevant to consider a broader familythat also includes prolyl
oligopeptidase (PREP; EC 3.4.21.26), dipeptidyl peptidase II
(DPPII) (EC3.4.14.2), and prolyl carboxypeptidase (PRCP; EC
3.4.16.2). First, DPPII and PRCP share the α/βhydrolase fold with
the other DPPs and the catalytic triad is completely conserved in
both enzymes(2).Moreover, DPPII can cleave several DPPIV substrates
in vitro (3). Conversely, due to its substratepreference for
tripeptides (4), DPPII could actually be considered as a prolyl
carboxytripeptidase,emphasizing its similarities to PRCP. Another
argument for considering a broader family stems fromthe fact that
functional studies on the role of peptidases rely heavily on the
use of enzyme inhibitorsand many of the inhibitors used in earlier
studies are now known to inhibit more than one familymember. For
example, early studies on DPPIV used inhibitors which we now know
also inhibitDPPII, DPP8, DPP9, FAP, and/or PREP due to their
sequential and/or structural similarity [e.g., Ref.(5–9)]. PRCP is
known to be inhibited by KYP-2047 and Z-Pro-Prolinal at higher
concentrations,
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3871
http://www.frontiersin.org/Immunology/http://www.frontiersin.org/Immunology/editorialboardhttp://www.frontiersin.org/Immunology/editorialboardhttp://dx.doi.org/10.3389/fimmu.2015.00387https://creativecommons.org/licenses/by/4.0/mailto:[email protected]://dx.doi.org/10.3389/fimmu.2015.00387http://www.frontiersin.org/Journal/10.3389/fimmu.2015.00387/abstracthttp://www.frontiersin.org/Journal/10.3389/fimmu.2015.00387/abstracthttp://www.frontiersin.org/Journal/10.3389/fimmu.2015.00387/abstracthttp://www.frontiersin.org/Journal/10.3389/fimmu.2015.00387/abstracthttp://www.frontiersin.org/Journal/10.3389/fimmu.2015.00387/abstracthttp://loop.frontiersin.org/people/223666/overviewhttp://loop.frontiersin.org/people/257600/overviewhttp://loop.frontiersin.org/people/199769/overviewhttp://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
which have often been used for the functional study of
PREP[e.g., Ref. (10–12)]. Table 1 summarizes the most commonlyused
DPP inhibitors and their selectivity compared to DPPIV.In view of
the aforementioned reasons and for the sake of
simplicity, we will use “DPP family” as a blanket term,
whichincludes DPPII, PRCP, and PREP even though strictly speak-ing
they are not DPPs. Figure 1 provides a general overviewof this
broadly defined DPP family. The roles of various family
TABLE 1 | Overview of commonly used inhibitors within the DPP
family and the ratio of inhibitor needed to inhibit the respective
DPP family membercompared to what is needed to inhibit DPPIV.
Inhibitors DPPII DPP8 DPP9 FAP PREP PRCP Reference
Clinical Alogliptin >14,000 >14,000 >14,000 >14,000
>14,000 ND (16)Linagliptin >100,000 40,000 >10,000 89
>100,000 ND (17)Saxagliptin >50,000 390 77 >4,000 ND ND
(18)Sitagliptin >5,550 >5,550 >2,660 >5,550 >5,550
ND (19)Talabostat 4 8 4 3 44 NDVildagliptin >100,000 270 32 285
60,000 ND (20, 21)
Experimental 1G244 1
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
members in certain aspects of the immune system or
immunedysfunction have been reviewed in the past [e.g., Ref.
(13–15)]. In this review, we provide a comprehensive discussionand
update on the roles of DPPIV, DPPII, DPP8, DPP9, FAP,PREP, and PRCP
in the immune system and inflammatory dis-ease. We highlight the
role of these enzymes in atherosclerosis,a condition that lies at
the frontier between inflammation andcardiovascular disease, as the
DPP family encompasses possi-ble therapeutic targets for the
prevention and treatment of thisdisease.
A Brief Guide to the DPP Family
Dipeptidyl Peptidase IVThe prototypical DPP, DPPIV (often DPP4
in medical jargon)cleaves off an N-terminal dipeptide from peptides
with Pro orAla on the penultimate position. Its localization as a
solubleenzyme in body fluids, or anchored in the plasma membraneof
cells provides it with the necessary access to cleave a widerange
of bioactive peptides. As such, it can modify their biologi-cal
activity. Glucagon-like peptide (GLP)-1 and -2, and
glucose-dependent insulinotropic peptide (GIP) (29, 30), substance
P(31), neuropeptide Y (NPY) (32), stromal cell-derived factor-1α/β
(SDF-1α/β or CXCL12) (33), granulocyte macrophagecolony-stimulating
factor (GM-CSF) (1), CXCL10 (34–36), andhigh-mobility group box 1
(HMGB1) (37) have been identi-fied as physiological substrates,
while others, such as RANTES,have been proposed based on in vitro
experiments [e.g., Ref.(38)]. DPPIV also performs many of its
physiological func-tions through interactions with other proteins,
such as colla-gen, fibronectin, adenosine deaminase (ADA),
caveolin-1, andthe mannose-6-phosphate/insulin-like growth factor
II receptor(M6P/IGFIIR) (39–41). Some of those will be discussed in
moredetail below.
Dipeptidyl peptidase IV is well known for its role in
glucosehomeostasis. It has become a validated therapeutic target
for thetreatment of type 2 diabetes (T2D) (46). DPPIV inhibitors
reducethe rate of GLP-1 inactivation (Boxes 1 and 2). It has also
beenshown to be involved in cancer biology. The role of theDPP
familyin cancer has been addressed in several other reviews (39,
47–51).Finally, DPPIV has recently come back into the center of
attentionas the receptor for the MERS coronavirus (52).
BOX 1 Incretins.The incretins are a group of glucose-lowering
molecules produced by theintestines. The best known incretin is
glucagon-like peptide-1 (GLP-1). Thisincretin is derived from
proglucagon and secreted after a meal from L-cellsin the distal
ileum and colon. In the pancreas, it induces insulin secretion
andbiosynthesis while lowering glucagon secretion. In addition,
GLP-1 increasesthe β-cell mass, thereby restoring insulin
production. It is clear that GLP-1also has functions outside
glucose metabolism. Its receptor, GLP-1-R, is notonly found in the
pancreas but also expressed in brain, lung, kidney, stomach,and
heart (42, 43). Recently, it was shown that stimulation after
myocardialinfarction reduces the infarct size (44, 45). Currently,
GLP-1 agonists areapproved for the treatment of type 2 diabetes.
These incretin mimetics seemto have a slightly better efficacy as
DPPIV inhibitors and lead more frequentlyto weight loss.
Unfortunately, an important drawback for their therapeutic useis
that they can only be administered by subcutaneous injection
(46).
Fibroblast Activation Protein αααFibroblast activation protein
α, also known as seprase can presentitself as a type II
transmembrane protein or as a shedded plasmaprotease (57). In the
latter case, it is also known as antiplasmin-cleaving enzyme, which
converts α2-antiplasmin into a moreactive form, suppressing
fibrinolysis (58). Some of the knownDPPIV substrates were later
found to be cleaved in vitro byFAP as well (59), though any
physiological relevance remainsunclear.
Unlike DPPIV, FAP also possesses a gelatinase activity.
Thisenables FAP to degrade proteins of the extracellular matrix
(60).This is of particular interest with regard to its involvement
ina number of pathological processes (47). FAP is highly
inducedduring inflammation, activation of hepatic stellate cells in
liver cir-rhosis and strongly expressed bymesenchymal cells of
remodelingtissue (47, 61). FAP is also a key regulator during tumor
growthand metastasis (47). As all these processes require
degradation ofthe extracellular matrix, FAP’s involvement in these
pathologiesis most likely associated with its gelatinase activity
(51). Its rolein cancer biology has been reviewed before (47, 62).
It is inter-esting to note that, so far, in clinical trials
Talabostat has shownminimal or no clinical benefit for the
treatment of metastaticcolorectal cancer, advanced non-small cell
lung cancer, or stageIV melanoma (63–65). It should be mentioned,
however, thatTalabostat is a broad-range inhibitor also targeting
DPPIV, DPP8,and DPP9.
Dipeptidyl Peptidases 8 and 9Dipeptidyl peptidases 8 and DPP9
show DPPIV-like activity andshare a very high-sequence similarity
to each other (77% aa sim-ilarity, 57% aa identity) (24). These
cytoplasmic enzymes haveseveral isoforms. It has been a matter of
debate whether all areexpressed as protein in cells and, if so,
whether they are active(66–69). Interestingly, the N-terminal
extension of the longerDPP9 variant contains a nuclear localization
signal and, indeed,this form localizes to the nucleus (69). DPP8
has been shown tocleave a number of DPPIV chemokine substrates in
vitro (70).Another DPPIV substrate, NPY, has indirectly been shown
to be
BOX 2 DPPIV inhibitors.Dipeptidyl peptidase IV inhibitors
prolong the biological half-life of the incretinsand are therefore
used for the treatment of type 2 diabetes.
Sitagliptin,vildagliptin, saxagliptin, linagliptin, and alogliptin
are DPPIV inhibitors currentlyavailable on the market for treatment
of type 2 diabetes. Sitagliptin andalogliptin are highly selective
toward DPPIV in vitro, whereas vildagliptin andsaxagliptin are less
selective with regard to DPP8 and 9, and linagliptin withregard to
FAP (28). Their clinical efficacy and safety in the use of type
2diabetes seem comparable as far as can be judged from the data
available.
There is a growing interest toward a use outside type 2 diabetes
as it hasbecome clear that DPPIV inhibitors have pleiotropic
effects. While negativeeffects have been found in heart failure
(53), some studies suggest them asa possible therapeutic strategy
in cardiovascular pathologies (28, 54). TheSITAGRAMI trial and
follow-up studies revealed that the combination of aDPPIV inhibitor
with granulocyte-colony-stimulating factor or in
monotherapypresents a therapeutic option after myocardial
infarction (55, 56). As statedabove, the mechanism is not yet clear
but may be explained by a longerbiological half-life of DPPIV
substrates, glucagon-like peptide-1, B-type natri-uretic peptide,
and stromal cell-derived factor-1 α/β. All three peptides havea
cardioprotective effect that is abolished by DPPIV-mediated
cleavage. Foran extensive review of the involved substrates, see
Matheeussen et al. (43).
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3873
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
a DPP8 and DPP9 substrate as well (71). Efforts have been madeto
find intracellular DPP8 and 9 substrates using a peptidomicapproach
(72), but so far it has been hard to attribute
physiologicalrelevance to the possible substrates beyond the role
of DPP8 and9 in intracellular peptide turnover (73).
The physiological functions of DPP8 and DPP9 are still
notproperly understood.Mainly, a lack of available knockout
animals,specific inhibitors, and substrates has hampered progress
(24).A mouse model has been established with a targeted
inactiva-tion of DPP9 enzymatic activity (74), but homozygous
DPP9-inactive neonates die within 8–24 h after birth. Despite these
lim-itations, some indications toward their role are surfacing.
Usingimmunohistochemistry, DPP8 and 9 were found associated
withspermatozoids and spermatids and the short mRNA of DPP8is
predominantly expressed in testes (75, 76), suggesting a rolein
spermatogenesis and male fertility. Recent work has foundSUMO1 to
be an allosteric activator of DPP9 (77), whereas a smallpeptide
corresponding to the interaction surface of SUMO1 is
anon-competitive inhibitor of DPP8 and DPP9 (78). A genome-wide
association study has linked DPP9 to idiopathic pulmonaryfibrosis
(79).
Finally, a number of studies have shown a role for DPP8 andDPP9
in apoptosis (71, 80–83). Two studies showed that overex-pression
enhanced induced apoptosis and impaired cell adhesionand migration
(80, 81). Conversely, DPP8/9 inhibition in tumorcells decreased the
number of viable cells because of a decreasedcleavage of
pro-apoptotic NPY (71). In macrophages, inhibitioncaused a
marginal, yet significant increase in apoptosis, indepen-dent of
NPY cleavage (82). Interestingly, vildagliptin, a DPPIVinhibitor
already on the market to treat type 2 diabetes, but withpoorer
selectivity toward DPP8 and 9, was shown to enhanceparthenolide’s
anti-leukemic activity through its inhibition ofDPP8 and 9, and not
DPPIV (83).
Dipeptidyl Peptidase II and ProlylCarboxypeptidaseProlyl
carboxypeptidase, also called angiotensinase C or lyso-somal Pro-X
carboxypeptidase, is a lysosomal carboxypeptidasesharing strong
sequence homology with the likewise lysosomalDPPII (4, 84). PRCP
preferentially cleaves off the C-terminalamino acid when Ala or Pro
is in the penultimate position, whileDPPII targets N-terminal X-Pro
or X-Ala dipeptides (85, 86). Inaddition to a structural
similarity, PRCP and DPPII have partiallyoverlapping substrate
specificities due to DPPII’s preference fortripeptide substrates
(4). Perhaps surprisingly, Gly-Pro-pNA andAla-Pro-pNA, two typical
synthetic DPP substrates, have actuallybeen used to perform PRCP
activity measurements (87).
Prolyl carboxypeptidase is particularly known as one of thekey
enzymes of the renin–angiotensin system (RAS). It inactivatesthe
vasoactive peptides angiotensin II and angiotensin III bycleaving
off the C-terminal Phe (88). α-Melanocyt-stimulatinghormone 1–13,
an anorexigenic neuromodulator, is inactivatedby PRCP, implying a
role in body weight control (89). Basedon the involvement of PRCP
in the conversion of these peptidehormones, the enzyme has also
been associated with diseases,such as hypertension, diabetes
mellitus, obesity, inflammation,and cardiovascular dysfunction (90,
91).
Dipeptidyl peptidase II has no known natural substrates.
TheDPPIV substrate substance P has been shown to be cleavedby DPPII
in vitro (3), but much less efficiently, casting doubtover any
physiological relevance. It has been shown that inhi-bition or
silencing of DPPII causes apoptosis of quiescentG0 lymphocytes
(92–94). On the other hand, a highly spe-cific DPPII inhibitor,
UAMC00039, did not induce apopto-sis, autophagy, or necrosis in
human leukocytes (25, 95), butthis study did not specifically look
at quiescent cells or lym-phocytes. Finally, changes in DPPII
activity levels have beenobserved in a number of pathologies, such
as neurodegenera-tive disorders, myopathies, cancer, and
gastro-intestinal disor-ders (4).
Prolyl OligopeptidaseProlyl oligopeptidase is an oligopeptidase
with endopeptidaseactivity. It has been shown to be localized in
the cytoplasm (96–99), but given its ability to inactivate several
neuropeptides in vitroby limited proteolysis (100–115), its
involvement in the in vivogeneration of immunoactive peptides
N-acetyl-prolyl-glycyl-proline and
N-acetyl-seryl-aspartyl-lysyl-proline (116, 117), andits presence
in plasma (118, 119), it most likely also has anextracellular
role.
Initial interest for PREP derived from the positive effects
ofPREP inhibitors on scopolamine-induced amnesia in rats (120–123).
PREP inhibition was also found to promote neuronal sur-vival and
neurite outgrowth of cerebellar granule cells (124). How-ever, a
recent study in mice shows that the lack of PREP in vivocauses a
reduction of synaptic spine density in the hippocampalregion along
with reduced long-term potentiation and memoryfunctions (125).
Many of PREP’s functions aremediated through its
interactionswith other proteins. PREP is known to interact with
GAP-43 (126,127), α-tubulin (96), and GADPH (128). Its most studied
inter-action is with α-synuclein (126), reviewed in Ref. (129).
PREPand α-synuclein have been shown to co-localize in cell models
ofstress and in the substantia nigra of post-mortem Parkinson’s
dis-ease brain (11, 130). In vitro, the aggregation rate of
α-synucleinincreases in the presence of high concentrations of
PREP, whichis abolished through active site inhibitors of PREP and
absentwith a catalytically impaired PREP mutant (131). In vivo,
PREPinhibition reduces α-synuclein aggregates in a cellular and
animalmodel for Parkinson’s disease (11).
The DPP Family in the Immune System
The DPP Family in the Innate Immune SystemDPP Family Members in
Monocytes andMacrophagesThe role of DPPIV in monocytes and
macrophages has beensomewhat contested. Whereas DPPIV’s presence on
monocytesand macrophages has been shown repeatedly in mice and
rats(132–134), its expression in human monocytes and macrophagesis
less obvious. Figure 2 shows an overview of the expres-sion of
DPPIV throughout the immune system. In visceral obe-sity, DPPIV
expression is low on peripheral blood monocytes,macrophages, and
dendritic cells, but it is upregulated in vitro
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3874
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
FIGURE 2 | Summary of CD26/DPPIV expression in cells of the
immune system.
after differentiation and activation of isolated monocytes
intomacrophages or dendritic cells, and in vivo locally in adipose
tissue(135). Interestingly, the authors showed that macrophage- or
den-dritic cell-associated DPPIV most likely binds ADA,
promotinglocal degradation of adenosine, a T-cell proliferation
suppressor,thereby inducing T-cell proliferation (135). Three other
studiesalso found no to low DPPIV expression or activity associated
withhuman monocytes and/or macrophages (82, 136–138). Othershave
investigated DPPIV in monocyte- or macrophage-like celllines (136,
137, 139–144). In HL-60 cells, its expression has beenfound to be
regulated by differentiation into macrophage-likecells (139). DPPIV
inhibitor alogliptin can affect ERK activa-tion, MMP1 and IL-6
secretion in U937 cells (140, 141). How-ever, these studies
employed alogliptin at concentrations lowerthan its IC50 for DPPIV.
It is therefore questionable whetherthe observed effects were
mediated by DPPIV at all. On theother hand, proliferation is
reduced in the presence of a DPPinhibitor in U937 cells expressing
high levels of DPPIV, butnot in the same cell type expressing low
levels of DPPIV (144).Moreover, the same inhibitor causes the
former cells to secretelower amounts of IL-1β, but higher amounts
of TNFα (144).It could be that inhibition merely increases TNFα’s
half-life, asDPPIV has been implicated in its degradation in U937
cells (137).In THP-1 cells, DPPIV inhibitors alogliptin and
sitagliptin bothreduced these cells’ chemotactic potential (142).
DPPIV inhibitorssitagliptin and NVPDPP728 also reduced NLRP3, TLR4,
andIL-1β expression and increased GLP-1R expression in THP-1cells
and this effect was blocked through PMA differentiation(143).
Importantly, such cell lines have been derived from differ-ent
types of myeloid leukemia, and as it is known that DPPIV
expression is often dysregulated in cancer (47–51), the
physio-logical relevance of these findings remains uncertain. FAP
hasbeen shown on tumor-associated macrophages in human breastcancer
(145).
Dipeptidyl peptidase 8/9 activity has been found in
humanmonocytes and U937 cells (136). DPP8 was found associatedwith
activated microglia/macrophages in a rat model of cere-bral
ischemia (146). DPP8 and 9 are abundantly present inmacrophage-rich
regions of atherosclerotic plaques (82). Interest-ingly, DPP9 is
upregulated after in vitromonocyte-to-macrophagedifferentiation.
Moreover, inhibition or RNA silencing of DPP9attenuates
pro-inflammatory M1, but not M2, macrophage acti-vation (82).
In rats, DPPII is expressed in tissue-residentmacrophages
(147,148). Humans show DPPII activity in monocytes as well as
U937cells (25, 136). Human blood derived alveolar macrophages
showhigh-PRCP activity (138, 149). Interestingly, in a mouse in
vivoangiogenesis assay, macrophage infiltration into the wound
wasincreased in mice with a PRCP deletion (150).
Prolyl oligopeptidase activity has been shown in mouse andrat
peritoneal macrophages and in rat pulmonary macrophages(134, 151,
152). Its activity in mouse peritoneal macrophages isincreased
after thioglycollate ellicitation (134). In addition, PREPhas been
identified as a neurotoxic component in the supernatantof activated
THP-1 cells, which are monocyte-like cells (153).Apparently, these
cells secrete PREP upon activation with IFNγand LPS and partly
because of this, their supernatant is toxic toneuroblastoma SH-SY5Y
cells, as shown through the use of PREP-specific inhibitors (153).
PREP’s mode of action in this remainsunclear.
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3875
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
DPP Family Members in GranulocytesRecently, a study showed that
DPPIV acts as a chemorepellentfor human and murine neutrophils
(154). Adding recombinantDPPIV to purified human neutrophils in an
Insall chamber causesthe neutrophils to migrate away from the
higher concentrationof DPPIV. This effect is blocked by DPPIV
inhibitors, meaningthat the effect is mediated through DPPIV’s
enzymatic activity,although a candidate substrate is not obvious.
Moreover, in amouse model of acute respiratory distress syndrome,
oropharyn-geal aspiration of DPPIV prevented accumulation of
neutrophilsin the lung (154). By contrast, PREP is involved in the
generationof prolyl-glycyl-proline, a collagen fragment that is an
efficientneutrophil chemoattractant (155). Human peripheral blood
neu-trophils contain PREP activity and are themselves capable
ofgenerating prolyl-glycyl-proline after LPS-activation, alluding
to aself-sustaining pathway of neutrophil inflammation (116).
PRCPis also abundantly expressed in human neutrophils (90).
The recruitment of eosinophils is affected by DPPIV
activity.CCL11, also known as eotaxin, is a DPPIV substrate and
cleavageby DPPIV prevents the activation of its receptor CCR3
(156).In rats, it was shown that administration of CCL11 results
ineosinophil recruitment and this recruitment is significantly
moreeffective in DPPIV-deficient F344 mutants (156).
Finally, DPPII activity has been reported in the granules ofmast
cells in several publications (147, 148, 157). It is releasedfrom
peritoneal mast cells upon degranulation and is apparentlyinhibited
by histamine and Zn2+ at concentrations present in thegranules of
mast cells (157).
DPP Family Members in Natural Killer CellsDipeptidyl peptidase 4
is present in low amounts on freshly iso-lated human NK cells and
its expression is only upregulated in asmall subpopulation after
IL-2 stimulation (158). In that study, itwas also shown that DPPIV
inhibition suppresses DNA synthesisand cell cycle progression of NK
cells, but these effects may beDPP8/9 mediated as the inhibitors
used in that study are nowknown to also inhibit DPP8/9 activity
(159). Another study showsthat DPPIV is actually only expressed by
a small subpopulationof peripheral NK cells (160). The natural
cytotoxicity of NK cellsis not influenced by the presence or
absence of DPPIV on theircell surface (158, 160). However,
DPPIV-negative NK cells showsignificantly less CD16-dependent lysis
than DPPIV-positive NKcells (160). Interestingly, NK cytolytic
function against tumorcells was diminished in DPPIV-deficient rats
in a model for lungmetastasis (161).
Figure 3 shows an overview of published data on the DPPfamily in
the innate immune system.
The DPP Family in the Adaptive ImmuneResponseDPP Family Members
in Humoral ImmunityOnly about 5% of freshly isolated CD20-positive
B cells expressDPPIV, but this fraction grows significantly upon
pokeweedmito-gen (PWM) or S. aureus protein stimulation (162).
Similar toNK cells, DPPIV inhibitors significantly suppress DNA
synthe-sis in B-lymphocytes (162), but again these inhibitors are
nowknown to also inhibit DPP8 and 9 (159). Mouse spleen-derived
B-lymphocytes only express low amounts of DPPIVmRNA (163).DPP8
and 9 mRNA, on the other hand, are expressed at muchgreater levels
in these cells, and they are upregulated in Raji cells,a
B-lymphocyte-like cell line, after PWM, LPS stimulation ormitomycin
c treatment, and downregulated after DTT treatment(163). DPP8 and 9
have also been shown immunohistochemicallyin human lymph follicular
lymphocytes (164). DPPII activity hasalso been shown in human
B-lymphocytes (25).
DPP Family Members in Cell-Mediated ImmunityDipeptidyl peptidase
IV was originally described as a surfacemarker for T-lymphocytes,
in which case it is better known asCD26, and later more
specifically for a subset of CD4-positivememory cells, CD4+ CD45RO+
CD29+ cells, which respondmaximally to recall antigen tetanus
toxoid and induce B-cell IgGsynthesis (165, 166). Indeed, CD26
surface expression is aug-mented along with the antigen sensitivity
of a particular CD4+T-cell clone (167). CD26high CD8+ T-cells
belong to the earlyeffector memory T-cell subset (168). CD26 is
also a marker forT-cell activation (165, 169–171). CD26 expression
on CD4+ T-cells correlates with TH1 responses. Stimuli that
typically inducea TH1 phenotype tend to induce CD26 expression
(172). Addi-tionally, the CD4+ T cells capable of transendothelial
migrationin vitro are characterized by a bright expression of CD26
(173,174), but CD26 does not seem to be actually involved in
T-celladhesion to endothelial cells or fibroblasts (175). Recently,
it wasshown that up to 98% of all TH17 cells show very high
CD26expression, with mean fluorescent intensity on these cells
almosttwice as high as on TH1 or TH2 cells. Therefore, the authors
of thisstudy suggest CD26 as a marker for TH17 cells (176).
Conversely,CD26 has been proposed as a negative marker for the
selectionTreg cells due to its very low-surface expression on these
cells(176–178).
CD26 is also a costimulatory molecule for T-cell
activation.Crosslinking of CD26, along with CD3, stimulates T-cell
activa-tion and proliferation (168, 179, 180). CD26 can also
directly acti-vate T-cells in an alternative activation pathway,
but this requiresthe presence of the TCR/CD3 complex (181–183).
During cos-timulation, CD26 is mannose-6 phosphorylated and
internalized,the latter of which is mediated in part by its
interaction withM6P/IGFIIR (184). It then localizes to lipid rafts
where it mightinteract with CD45, required for TCR signaling,
facilitating co-localization of this molecule with TCR signaling
molecules (185,186). A number of candidate binding partners for
costimula-tion have been proposed. ADA and CD26 are known
bindingpartners (187). Even though ADA binding to CD26 does notseem
to be essential for immune functions in humans (188),the nanomolar
affinity of this interaction probably reflects itsimportance (189).
Indeed, association with free ADA or ADApresented by ADA-anchoring
proteins on dendritic cells seemsto costimulate T-cells through
CD26 binding (190, 191). On theother hand, it has been shown that
soluble DPPIV enhances T-cellproliferation independent of its
enzyme activity or ADA-bindingcapability (192). Interestingly, the
ADA–CD26 interaction canbe inhibited by HIV-1 external envelope
protein gp120 and thisrequires interaction of gp120 with CXCR4
(189). In fact, evi-dence suggests a physical association between
CXCR4 and CD26
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3876
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
FIGURE 3 | Overview of the expression and function of individual
DPP family members in the innate immune system. Expression-based
evidenceis in italic.
on peripheral blood lymphocytes (193). Fibronectin is
anotherknown binding partner of CD26 involved in T-cell
costimulation(194–196). Finally, CD26 interacts with caveolin-1 on
monocytes.
This interaction causes an upregulation of CD86 on these
cells,which potentiates antigen-specific T-cell activation (197).
Moststudies seem to find no need for DPPIV’s enzymatic activity
for
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3877
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
succesful costimulation, as evidenced through the use of
inhibitorsand catalytically impaired DPPIV mutants (198–201).
Dipeptidyl peptidase 8 and 9 are present in baboon
spleeninterfollicular T-lymphocytes and Jurkat T cells (164). They
areupregulated in the latter after PWM and LPS, but not PHA,
stim-ulation (163, 202, 203). Activation of PWM-stimulated T-cells
issuppressed after DPPIV/8/9 inhibition. Moreover, DNA
synthesisandT-cell proliferation are reduced, aswell as production
of IL-2, -10, -12, and IFN-γ. This is due to an induction of TGF-β
secretion(159, 204–207). Inhibition also upregulates CTLA-4 and
down-regulates DPPIV expression (206, 208). These observations
mightbe physiologically relevant as endogenous inhibitors of DPPs
areknown which have similar effects in cell-based experiments as
thesynthetic inhibitors (209, 210).
Dipeptidyl peptidase II activity is higher in T-lymphocytes
thanin B-lymphocytes (25) and absence ofDPPII steers
T-lymphocytestoward a TH17 phenotype. T-lymphocytes of DPPII KO
mice
hyperproliferate and secrete IL-17 after CD3 crosslinking or
afterin vivo priming and in vitro antigen-specific restimulation
(211).PREP activity has also been shown inmouse T-lymphocytes
(212).Its activity is significantly higher in immature,
double-positivethymocytes compared to mature, single-positive
thymocytes, orperipheral T-cells. T-cells stimulated with Con A
followed byIL-2 show a time-dependent increase in PREP activity and
pre-treatment of cells with a PREP inhibitor renders them resistant
toactivation-induced cell death (212).
Figure 4 shows an overviewof in vitrodata onDPP involvementin
primary human T cell activation.
The DPP Family in Inflammatory Disease
The DPP family has been reported to be dysregulated or
eveninvolved in a number of inflammatory disorders. Expression
levelsof a number of family members are modulated in rheumatoid
FIGURE 4 | Overview of in vitro data on DPP involvement
inprimary human T cell activation. (A) M6P/IGFIIR associates
withmannose-6-phosphorylated DPPIV causing it to associate with
CD45in lipid rafts. This facilitates co-localization with the TCR
signalingmolecules for T cell costimulation. (B) Interaction of ADA
presented byADA-anchoring proteins on dendritic cells with DPPIV on
T cells
causes costimulation. (C) Interaction of DPPIV on T cells
withcaveolin-1 on monocytes induces the expression of CD86 on
thelatter. Interaction of CD86 with CD28 costimulates T cells.
(D)Inhibition of DPP8/9 induces TGFβ in PWM-stimulated T cells.
TGFβattenuates T cell activation. (E) Inhibition or absence of
DPPII steers Tcells toward TH17 differentiation.
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3878
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
arthritis. Whereas the density of CD26 on peripheral T cells
isincreased in patients, it is low on synovial fluid T cells
(213–215).DPPIV activity in plasma, serum, or synovial fluid of
patientshas also been found to be decreased, similar to results in
severalrat models of arthritis (216–222). Interestingly, rats
resistant toinduction of arthritis show higher plasma DPPIV levels
(222).By contrast, DPPII and PREP activity are increased in serumor
synovial fluid of arthritis patients (219–221). Likewise,
FAPimmunoreactivity is much higher in fibroblast-like
synoviocytesof rheumatoid arthritis patients compared to
osteoarthritis con-trols (223). DPPIV’s involvement in rheumatoid
arthritis has beenstudied, but remains unclear. On the one hand,
inhibition cansuppress development of arthritis in rats (224).
Note, however,that effects mediated through other DPPs are hard to
excludeas these inhibitors were developed before DPP8 and DPP9
werediscovered. On the other hand, induced arthritis is more
severein DPPIV-deficient mice (216). This may be due to
increasedlevels of circulatingCXCL12 (216), aDPPIV substrate shown
to beinvolved in rheumatoid arthritis. Several case reports in
patientsseem to suggest a link between the development of
rheumatoidarthritis and the use of DPPIV inhibitors (225–227). PRCP
hasalso been associated with rheumatoid arthritis as its activity
wasshown in synovial fluid isolated from arthritic joints
(149).
Inflammatory bowel disease shows a distinct expression patternof
the DPP family. DPPIV serum or plasma activity seems tobe lower in
patients, whereas there is an increase of circulatingCD26+CD25+
cells with a higher CD26 surface expression (228,229). FAP is
heavily expressed bymyofibroblasts in the submucosastrictures in
Crohn’s disease, and is upregulated after stimulationwith TNFα or
TGFβ (230). In a mouse model, colonic DPPIIand DPP8 mRNA and DPPII
activity are increased, while colonicDPP8/9 activity only increases
significantly in mice that are alsoDPPIV knockouts (231). In mouse
models, inhibition or abroga-tion of DPPIV seems to at least
partially ameliorate symptoms,possibly by increasing circulating
GLP-2, impairing neutrophilrecruitment, and maintaining Treg
populations (231–236). Someof those beneficial effects may be
mediated in part by the otherDPPs, as additive effects were found
for DPPIV KO and theDPP inhibitors (231, 234, 237). A recent study
suggests that theameliorative effects of DPP inhibitors aremost
likely notmediatedthrough GLP-2 protection (238).
The DPP family has also been studied in
neuroinflammation.Ischemia-induced neuroinflammation in rats
prompts a distinctexpression and activity pattern of the DPPs. In
the days followingischemia, the brain of these rats undergoes a
complex reorgani-zation of DPP expression with changes in mRNA,
protein, andactivity levels of DPPII, 4, 8, and 9 in cortical
neurons, microglia,and macrophages (146). Similarly, PREP seems to
be associatedwith astrocytes and microglia in lesioned inflamed
brains of rats(239).DPPIV andPREP alsomay be involved inmultiple
sclerosis.CD26+ T cells were found to correlate with disease scores
(240).SolubleDPPIV levels are elevated in cerebrospinal fluid of
patients(241). Plasma PREP activity, on the other hand, is lower in
patientswith relapsing–remitting or primary progressivemultiple
sclerosisand in clinically isolated syndrome (118, 119).
Interestingly, PREPinhibition seems to aggravate symptoms in a
mouse model ofmultiple sclerosis (118).
In systemic lupus erythematosus, DPPs also seem to be
dysreg-ulated. In mouse models, DPPII and PREP activities are
increasedin plasma, spleen, kidney, and liver, whereas DPPIV
activity isdecreased (221, 242). Human patients also show elevated
DPPIIand reduced DPPIV activities in serum, along with reduced
num-bers of CD26+ T cells (221, 243). Interestingly, serum
DPPIVlevels are inversely correlated with disease score (243).
FAPimmunoreactivity is decreased in the synovium of lupus
patients(244).
Finally, DPPIV has been studied in psoriasis, an immune-mediated
chronic inflammatory disorder with primary involve-ment of skin and
joints. Its mRNA, protein levels and activity arehigher in
psoriatic skin samples (245, 246). By contrast, serumDPPIV levels
and activity seem to be lower in patients (247,248), accompanied by
a reduction of peripheral CD8+CD26+T cells (249, 250). Two case
reports suggest a link betweenthe use of DPPIV inhibitor
sitagliptin and psoriasis. While onewoman developed a psoriaform
eruption 6 days after startingsitagliptin treatment (251), another
patient’s psoriatic lesionsgradually diminished and were
effectively gone 3months after thestart of sitagliptin treatment
(252).
The DPP Family in Atherosclerosis
Dipeptidyl peptidase IV has recently received much attention
forits potential as a therapeutic target for the treatment of
atheroscle-rosis (Box 3) (253). This is not surprising considering
the cur-rent use of DPPIV inhibitors in the treatment of T2D and
thefact that T2D is associated with a higher risk for
atherosclero-sis (28, 254). In the ApoE−/− mouse model of
atherosclerosis,DPPIV inhibition generally reduces plaque area and
monocyteand macrophage plaque infiltration (255–257). A reduction
inthe number of plaque lesions or in smooth muscle cell contenthave
also been observed (255, 256), as well as lower plaqueMMP9 and
higher plaque collagen levels, suggesting increasedplaque stability
(258). One study reported effects of DPPIV inhi-bition on
atherosclerotic plaques of only diabetic ApoeE−/− mice(141), but
more recently, Terasaki et al. found similar effectsin non-diabetic
and diabetic ApoE−/− mice (259). Likely, suchdifferences can be
explained by the fact that different DPPIVinhibitors were employed.
Effects of DPPIV on atherogenesissimilar to those observed in
ApoE−/− mice have been reproducedin LDLR−/− mice (142, 260). In
human atherosclerotic plaques,
BOX 3 Atherosclerosis.Atherosclerosis is the most common
underlying cause of cardiovasculardiseases and should be regarded
as an inflammatory disease. It startswith dysfunction of the
endothelium leading to the expression of leukocyteadhesion
molecules, such as selectins and integrins. Locally produced
pro-inflammatory cytokines attract the immune cells into the inner
layer of theendothelium. However, not only leukocytes are found in
the plaque butalso low-density lipoprotein particles (LDL) and
their oxidized counterparts(oxLDL). In the plaque, monocytes
differentiate into macrophages, phagocy-tose the oxLDL and turn
into so-called pro-atherogenic foam cells. This pro-cess leads to a
self-sustaining, local inflammation leading to plaque growth,and
migration of smooth muscle cells into the core. A plaque is defined
asstable as long as it is contained by a thick fibrous cap.
However, the latteris slowly degraded by the proteolytic enzymes
from the leukocytes. Thiseventually leads to rupture and the
formation of arterial thrombi (264, 265).
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 3879
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
DPPIV immunoreactivity could only be found on endothelium
ofneovessels (82). It was recently found thatDPPIV activitymay be
apredictor for the onset of atherosclerosis in otherwise healthy
Chi-nese individuals (261). Another prospective study investigated
theinfluence of vildagliptin or sitagliptin treatment on
intima-media
thickness, a surrogate marker for atherosclerosis. This
studyfound that treatment with vildagliptin or sitagliptin
reducedintima-media thickness, suggesting that DPPIV inhibition
mightbe beneficial in atherosclerosis in humans as well (262).
More-over, treatment naïve T2D patients treated with alogliptin
FIGURE 5 | Dipeptidyl peptidase inhibition as a putative
strategyfor the treatment of atherosclerosis. (1) DPP9 inhibition
wouldattenuate M1 macrophage activation, reducing local
inflammation.Reduction in TNFα would reduce FAP on smooth muscle
cells (SMCs).This and FAP inhibition (2) would reduce collagen
degradation and
therefore plaque instability. PREP inhibition (3) would reduce
neutrophilinfiltration and consequently endothelial dysfunction and
furthermonocyte infiltration. DPPIV inhibition (4) would prevent
SMCproliferation, foam cell formation, endothelial dysfunction,
andmonocyte infiltration.
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 38710
http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
for 3months saw a significant decrease in their circulating
athero-genic lipids (263).
It has been suggested that DPPIV inhibitors’
anti-atherogeniceffects are mainly mediated through decreased
monocyte infil-tration, as DPPIV inhibitors suppress monocyte
activation andchemotaxis in vitro (142, 258). DPPIV inhibition also
reducesin vitro foam cell formation in exudate peritoneal
macrophagesfrom ApoE−/− mice (255). Moreover, soluble DPPIV
stimulatesin vitro proliferation of smooth muscle cells and this
can bereduced through the addition of a DPPIV inhibitor (256,
260).Finally, active circulating GLP-1 levels are augmented and
thisimproves endothelial dysfunction (259, 266). Probably,
DPPIVinhibition improves atherosclerosis through a combination
ofall these mechanisms. Indeed, incretin antagonists only
partiallyattenuate the anti-atherogenic effects of DPPIV
inhibition, sug-gesting that other mechanisms beyond incretin
preservation arein play (259). Interestingly, monocyte–endothelial
cell adhesion isabrogated by an anti-SDF-1α antibody in vitro
(267). LDL seemsto induce SDF-1α expression and leads to smooth
muscle cellproliferation and inhibition of cell apoptosis (267,
268). SDF-1α isa DPPIV substrate, which loses its biological
activity after cleavage(216). As DPPIV inhibition seems to improve
atherosclerosis,whereas intact SDF-1α appears to be deletorious, it
could beargued that SDF-1α cleavage by DPPIV does not play a major
rolein atherosclerosis.
Dipeptidyl peptidase 8 and 9 have been found to be
abundantlypresent in the macrophage-rich regions of human
atheroscleroticplaques and considering DPP9’s role in macrophage
activation, itmight potentially be involved in atherogenesis (82).
FAP expres-sion is enhanced in some, but not all types of human
atheromata.It is found on smooth muscle cells, and its expression
correlateswith macrophage burden, probably due to the fact that
TNFαupregulates FAP in smooth muscle cells in vitro. As it is
mainlyassociated with collagen-poor regions and can digest type I
col-lagen and gelatin in vitro, FAP probably contributes to
plaqueinstability (269).
Interestingly, many of the studies reviewed above show
thepotential of targeting DPP family members for the treatment
ofatherosclerosis (seeFigure 5). FAP inhibitionmight reduce
plaqueinstability by decreasing collagen breakdown; DPP9 inhibition
islikely to attenuate M1 macrophage activation, reducing the
localinflammatory cascade; DPPIV inhibition may decrease
monocyteinfiltration, foam cell formation, improve endothelial
dysfunc-tion, and reduce smooth muscle cell proliferation; and
finally,PREP inhibition might reduce neutrophil infiltration,
preventingendothelial dysfunction, and monocyte infiltration. All
of thisshows the possibilities of repositioning DPPIV inhibitors,
cur-rently being used to treat type 2 diabetes, as well as the
potentialof targeting other members of the DPP family.
Conclusion
Caution should be taken when interpreting results from
literaturedata based on DPP inhibitors, especially from older
studies. It isnowknown that, under the experimental conditions
used,many ofthese inhibitors are not specific for one particular
family member.The reported findings, however, remain interesting.
This reviewhas shown extensive involvement of members of the DPP
familyin the immune system. It is clear that these enzymes hold
greatpotential as targets for the treatment of certain inflammatory
dis-orders. Particularly, the possibility of targeting DPP family
mem-bers for the prevention and treatment of atherosclerosis
warrantsfurther investigation.
Acknowledgments
This work was supported by the University of
Antwerp(GOA2009–2012) and the Flanders Research Foundation
(FWO;Grant G0141.12). YW and KK are research fellows of the
FlandersResearch Foundation. Images were created based on
ServierMedical Art licensed under Creative Commons Attribution
3.0Unported License.
References1. Broxmeyer HE, Hoggatt J, O’Leary H, Mantel C,
Brahmananda C, Cooper
S, et al. Dipeptidylpeptidase 4 negatively regulates
colony-stimulating factoractivity and stress hematopoiesis. Nat Med
(2012) 18:1786–96. doi:10.1038/nm.2991.Dipeptidylpeptidase
2. Bezerra GA, Dobrovetsky E, Dong A, Seitova A, Crombett L,
ShewchukLM, et al. Structures of human DPP7 reveal the molecular
basis of specificinhibition and the architectural diversity of
proline-specific peptidases. PLoSOne (2012) 7:e43019.
doi:10.1371/journal.pone.0043019
3. Mentlein R, Struckhoff G. Purification of two dipeptidyl
aminopepti-dases II from rat brain and their action on
proline-containing neuropep-tides. J Neurochem (1989) 52:1284–93.
doi:10.1111/j.1471-4159.1989.tb01877.x
4. Maes M-B, Scharpé S, De Meester I. Dipeptidyl peptidase II
(DPPII), a review.Clin Chim Acta (2007) 380:31–49.
doi:10.1016/j.cca.2007.01.024
5. Stöckel-Maschek A, Mrestani-Klaus C, Stiebitz B, Demuth H,
Neubert K.Thioxo amino acid pyrrolidides and thiazolidides: new
inhibitors of prolinespecific peptidases. Biochim Biophys Acta
(2000) 1479:15–31. doi:10.1016/S0167-4838(00)00054-6
6. Coutts SJ, Kelly TA, Snow RJ, Kennedy CA, Barton RW, Adams J,
et al.Structure-activity relationships of boronic acid inhibitors
of dipeptidyl
peptidase IV. 1. Variation of the P2 position of Xaa-boroPro
dipeptides. J MedChem (1996) 39:2087–94. doi:10.1021/jm950732f
7. Belyaev A, Zhang X, Augustyns K, Lambeir AM, De Meester I,
VedernikovaI, et al. Structure-activity relationship of diaryl
phosphonate esters as potentirreversible dipeptidyl peptidase IV
inhibitors. JMedChem (1999) 42:1041–52.doi:10.1021/jm981033g
8. Senten K, Daniëls L, Van der Veken P, De Meester I, Lambeir
A-M, ScharpéS, et al. Rapid parallel synthesis of dipeptide
diphenyl phosphonate esters asinhibitors of dipeptidyl peptidases.
J Comb Chem (2003) 5:336–44. doi:10.1021/cc020096o
9. Van der Veken P, Senten K, Kertèsz I, De Meester I, Lambeir
A-M, Maes M-B, et al. Fluoro-olefins as peptidomimetic inhibitors
of dipeptidyl peptidases.J Med Chem (2005) 48:1768–80.
doi:10.1021/jm0495982
10. Myöhänen TT, Tenorio-Laranga J, Jokinen B, Vázquez-Sánchez
R, Moreno-Baylach MJ, García-Horsman JA, et al. Prolyl
oligopeptidase induces angio-genesis both in vitro and in vivo in a
novel regulatory manner. Br J Pharmacol(2011) 163:1666–78.
doi:10.1111/j.1476-5381.2010.01146.x
11. Myöhänen TT, HannulaMJ, Van Elzen R, GerardM, VanDer Veken
P, García-Horsman JA, et al. A prolyl oligopeptidase inhibitor,
KYP-2047, reducesα-synuclein protein levels and aggregates in
cellular and animal modelsof Parkinson’s disease. Br J Pharmacol
(2012) 166:1097–113. doi:10.1111/j.1476-5381.2012.01846.x
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 38711
http://dx.doi.org/10.1038/nm.2991.Dipeptidylpeptidasehttp://dx.doi.org/10.1038/nm.2991.Dipeptidylpeptidasehttp://dx.doi.org/10.1371/journal.pone.0043019http://dx.doi.org/10.1111/j.1471-4159.1989.tb01877.xhttp://dx.doi.org/10.1111/j.1471-4159.1989.tb01877.xhttp://dx.doi.org/10.1016/j.cca.2007.01.024http://dx.doi.org/10.1016/S0167-4838(00)00054-6http://dx.doi.org/10.1016/S0167-4838(00)00054-6http://dx.doi.org/10.1021/jm950732fhttp://dx.doi.org/10.1021/jm981033ghttp://dx.doi.org/10.1021/cc020096ohttp://dx.doi.org/10.1021/cc020096ohttp://dx.doi.org/10.1021/jm0495982http://dx.doi.org/10.1111/j.1476-5381.2010.01146.xhttp://dx.doi.org/10.1111/j.1476-5381.2012.01846.xhttp://dx.doi.org/10.1111/j.1476-5381.2012.01846.xhttp://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
12. Jalkanen AJ, Piepponen TP, Hakkarainen JJ, De Meester I,
Lambeir A-M,Forsberg MM. The effect of prolyl oligopeptidase
inhibition on extracellularacetylcholine and dopamine levels in the
rat striatum. Neurochem Int (2012)60:301–9.
doi:10.1016/j.neuint.2011.12.010
13. Ansorge S, Bank U, Heimburg A, Helmuth M, Koch G, Tadje J,
et al. Recentinsights into the role of dipeptidyl aminopeptidase IV
(DPIV) and aminopep-tidase N (APN) families in immune functions.
Clin Chem Lab Med (2009)47:253–61. doi:10.1515/CCLM.2009.063
14. Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase
inhibitors, anemerging drug class for inflammatory disease? Trends
Pharmacol Sci (2009)30:600–7. doi:10.1016/j.tips.2009.08.003
15. Ohnuma K, Dang NH, Morimoto C. Revisiting an old
acquaintance: CD26and its molecular mechanisms in T cell function.
Trends Immunol (2008)29:295–301. doi:10.1016/j.it.2008.02.010
16. Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel
DB, et al. Dis-covery of alogliptin: a potent, selective,
bioavailable, and efficacious inhibitorof dipeptidyl peptidase IV.
J Med Chem (2007) 50:2297–300. doi:10.1021/jm0703439
17. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F,
MarkM.
(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione
(BI 1356), a novelxanthine-based dipeptidyl peptidase 4 inhibitor,
has a superior potency andlonger duration of action compared with
oth. J Pharmacol Exp Ther (2008)325:175–82.
doi:10.1124/jpet.107.135723
18. Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A,
Robertson JG,et al. Discovery and preclinical profile of
saxagliptin (BMS-477118): a highlypotent, long-acting, orally
active dipeptidyl peptidase IV inhibitor for thetreatment of type 2
diabetes. J Med Chem (2005) 48:5025–37. doi:10.1021/jm050261p
19. Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, et
al.(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:
a potent, orally activedipeptidyl peptidase IV inhibitor for the
treatment of type 2 diabetes. J MedChem (2005) 48:141–51.
doi:10.1021/jm0493156
20. Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE,
Prasad K,et al.
1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine:
apotent, selective, and orally bioavailable dipeptidyl peptidase IV
inhibitor withantihyperglycemic properties. J Med Chem (2003)
46:2774–89. doi:10.1021/jm030091l
21. Wu J-J, Tang H-K, Yeh T-K, Chen C-M, Shy H-S, Chu Y-R, et
al. Biochemistry,pharmacokinetics, and toxicology of a potent and
selective DPP8/9 inhibitor.Biochem Pharmacol (2009) 78:203–10.
doi:10.1016/j.bcp.2009.03.032
22. Ryabtsova O, Jansen K, Van Goethem S, Joossens J, Cheng JD,
Lambeir A-M,et al. Acylated Gly-(2-cyano)pyrrolidines as inhibitors
of fibroblast activationprotein (FAP) and the issue of FAP/prolyl
oligopeptidase (PREP)-selectivity.Bioorg Med Chem Lett (2012)
22:3412–7. doi:10.1016/j.bmcl.2012.03.107
23. Jansen K, Heirbaut L, Cheng JD, Joossens J, Ryabtsova O, Cos
P, et al. Selectiveinhibitors of fibroblast activation protein
(FAP) with a (4-quinolinoyl)-glycyl-2-cyanopyrrolidine
scaffold.ACSMed Chem Lett (2013) 4:491–6. doi:10.1021/ml300410d
24. Van Goethem S, Matheeussen V, Joossens J, Lambeir A-M, Chen
X, DeMeester I, et al. Structure-activity relationship studies on
isoindoline inhibitorsof dipeptidyl peptidases 8 and 9 (DPP8,
DPP9): is DPP8-selectivity an attain-able goal? J Med Chem (2011)
54:5737–46. doi:10.1021/jm200383j
25. Maes M-B, Martinet W, Schrijvers DM, Van der Veken P, De
Meyer GR,Augustyns K, et al. Dipeptidyl peptidase II and leukocyte
cell death. BiochemPharmacol (2006) 72:70–9.
doi:10.1016/j.bcp.2006.04.009
26. Wilk S, Orlowski M. Inhibition of rabbit brain prolyl
endopeptidase by n-benzyloxycarbonyl-prolyl-prolinal, a transition
state aldehyde inhibitor. J Neu-rochem (1983) 41:69–75.
doi:10.1111/j.1471-4159.1983.tb11815.x
27. Rabey FM, Gadepalli RS, Diano S, Cheng Q, Tabrizian T,
Gailani D, et al.Influence of a novel inhibitor (UM8190) of
prolylcarboxypeptidase (PRCP)on appetite and thrombosis.CurrMedChem
(2012) 19:4194–206. doi:10.2174/092986712802430036
28. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the
treatment of type 2diabetes: a comparative review. Diabetes Obes
Metab (2011) 13:7–18. doi:10.1111/j.1463-1326.2010.01306.x
29. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of
glucose-dependentinsulinotropic polypeptide and truncated
glucagon-like peptide 1 in vitro
and in vivo by dipeptidyl peptidase IV. Endocrinology (1995)
136:3585–96.doi:10.1210/endo.136.8.7628397
30. Drucker DJ, Shi Q, Crivici A, Sumner-Smith M, TavaresW, Hill
M, et al. Regu-lation of the biological activity of glucagon-like
peptide 2 in vivo by dipeptidylpeptidase IV. Nat Biotechnol (1997)
15:673–7. doi:10.1038/nbt0797-673
31. Ahmad S, Wang L, Ward PE. Dipeptidyl(amino)peptidase IV and
aminopep-tidase M metabolize circulating substance P in vivo. J
Pharmacol Exp Ther(1992) 260:1257–61.
32. Frerker N, Wagner L, Wolf R, Heiser U, Hoffmann T, Rahfeld
J-U, et al. Neu-ropeptide Y (NPY) cleaving enzymes: structural and
functional homologuesof dipeptidyl peptidase 4. Peptides (2007)
28:257–68. doi:10.1016/j.peptides.2006.09.027
33. Proost P, Struyf S, Schols D, Durinx C, Wuyts A, Lenaerts
JP, et al. Processingby CD26/dipeptidyl-peptidase IV reduces the
chemotactic and anti-HIV-1 activity of stromal-cell-derived
factor-1alpha. FEBS Lett (1998)
432:73–6.doi:10.1016/S0014-5793(98)00830-8
34. Casrouge A, Decalf J, Ahloulay M, Lababidi C, Mansour H,
Vallet-pichard A,et al. Evidence for an antagonist form of the
chemokine CXCL10 in patientschronically infected with HCV. J Clin
Invest (2011) 121(1):308–17. doi:10.1172/JCI40594DS1
35. Rainczuk A, Rao JR, Gathercole JL, Fairweather NJ, Chu S,
Masadah R, et al.Evidence for the antagonistic form of CXC-motif
chemokine CXCL10 inserous epithelial ovarian tumours. Int J Cancer
(2014) 134:530–41. doi:10.1002/ijc.28393
36. Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll
MA, Albert ML.Dipeptidylpeptidase 4 inhibition enhances lymphocyte
trafficking, improvingboth naturally occurring tumor immunity and
immunotherapy. Nat Immunol(2015). doi:10.1038/ni.3201
37. Marchetti C, Di Carlo A, Facchiano F, Senatore C, De
Cristofaro R, Luzi A,et al. Highmobility group box 1 is a novel
substrate of dipeptidyl peptidase-IV.Diabetologia (2012) 55:236–44.
doi:10.1007/s00125-011-2213-6
38. Oravecz T, Pall M, Roderiquez G, Gorrell MD, Ditto M, Nguyen
NY, et al.Regulation of the receptor specificity and function of
the chemokine RANTES(regulated on activation, normal T cell
expressed and secreted) by dipeptidylpeptidase IV (CD26)-mediated
cleavage. J Exp Med (1997)
186:1865–72.doi:10.1084/jem.186.11.1865
39. Stulc T, Sedo A. Inhibition of multifunctional dipeptidyl
peptidase-IV: is therea risk of oncological and immunological
adverse effects? Diabetes Res ClinPract (2010) 88:125–31.
doi:10.1016/j.diabres.2010.02.017
40. Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH.
The roleof CD26/dipeptidyl peptidase IV in cancer. Front Biosci
(2008) 13:1634–45.doi:10.2741/2787
41. Tinoco AD, Tagore DM, Saghatelian A. Expanding the
dipeptidyl peptidase 4-regulated peptidome via an optimized
peptidomics platform. J Am Chem Soc(2010) 132:3819–30.
doi:10.1021/ja909524e
42. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP.
Gastroenterology(2007) 132:2131–57.
doi:10.1053/j.gastro.2007.03.054
43. Matheeussen V, Jungraithmayr W, De Meester I. Dipeptidyl
peptidase 4 asa therapeutic target in ischemia/reperfusion injury.
Pharmacol Ther (2012)136:267–82.
doi:10.1016/j.pharmthera.2012.07.012
44. Sonne DP, Engstrøm T, Treiman M. Protective effects of GLP-1
analoguesexendin-4 and GLP-1(9-36) amide against
ischemia-reperfusion injury in ratheart. Regul Pept (2008)
146:243–9. doi:10.1016/j.regpep.2007.10.001
45. Lønborg J, Vejlstrup N, Kelbæk H, Bøtker HE, Kim WY,
Mathiasen AB, et al.Exenatide reduces reperfusion injury in
patients with ST-segment elevationmyocardial infarction. Eur Heart
J (2012) 33:1491–9. doi:10.1093/eurheartj/ehr309
46. Drucker D, Nauck M. The incretin system: glucagon-like
peptide-1 receptoragonists and dipeptidyl peptidase-4 inhibitors in
type 2 diabetes. Lancet (2006)368:1696–705.
doi:10.1016/S0140-6736(06)69705-5
47. Kotačková L, Balážiová E, Šedo A. Expression pattern of
dipeptidyl peptidaseIV activity and/or structure homologues in
cancer. Folia Biol (2009) 84:77–84.
48. Bušek P, Malík R, Šedo A. Dipeptidyl peptidase IV activity
and/or structurehomologues (DASH) and their substrates in cancer.
Int J Biochem Cell Biol(2004) 36:408–21.
doi:10.1016/S1357-2725(03)00262-0
49. Arrebola Y, Gomez H, Valiente P, de los A Chavez M, Pascual
I. Dipep-tidyl peptidase IV and its implication in cancer.
Biotecnol Apl (2014) 31:102–10.
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 38712
http://dx.doi.org/10.1016/j.neuint.2011.12.010http://dx.doi.org/10.1515/CCLM.2009.063http://dx.doi.org/10.1016/j.tips.2009.08.003http://dx.doi.org/10.1016/j.it.2008.02.010http://dx.doi.org/10.1021/jm0703439http://dx.doi.org/10.1021/jm0703439http://dx.doi.org/10.1124/jpet.107.135723http://dx.doi.org/10.1021/jm050261phttp://dx.doi.org/10.1021/jm050261phttp://dx.doi.org/10.1021/jm0493156http://dx.doi.org/10.1021/jm030091lhttp://dx.doi.org/10.1021/jm030091lhttp://dx.doi.org/10.1016/j.bcp.2009.03.032http://dx.doi.org/10.1016/j.bmcl.2012.03.107http://dx.doi.org/10.1021/ml300410dhttp://dx.doi.org/10.1021/ml300410dhttp://dx.doi.org/10.1021/jm200383jhttp://dx.doi.org/10.1016/j.bcp.2006.04.009http://dx.doi.org/10.1111/j.1471-4159.1983.tb11815.xhttp://dx.doi.org/10.2174/092986712802430036http://dx.doi.org/10.2174/092986712802430036http://dx.doi.org/10.1111/j.1463-1326.2010.01306.xhttp://dx.doi.org/10.1111/j.1463-1326.2010.01306.xhttp://dx.doi.org/10.1210/endo.136.8.7628397http://dx.doi.org/10.1038/nbt0797-673http://dx.doi.org/10.1016/j.peptides.2006.09.027http://dx.doi.org/10.1016/j.peptides.2006.09.027http://dx.doi.org/10.1016/S0014-5793(98)00830-8http://dx.doi.org/10.1172/JCI40594DS1http://dx.doi.org/10.1172/JCI40594DS1http://dx.doi.org/10.1002/ijc.28393http://dx.doi.org/10.1002/ijc.28393http://dx.doi.org/10.1038/ni.3201http://dx.doi.org/10.1007/s00125-011-2213-6http://dx.doi.org/10.1084/jem.186.11.1865http://dx.doi.org/10.1016/j.diabres.2010.02.017http://dx.doi.org/10.2741/2787http://dx.doi.org/10.1021/ja909524ehttp://dx.doi.org/10.1053/j.gastro.2007.03.054http://dx.doi.org/10.1016/j.pharmthera.2012.07.012http://dx.doi.org/10.1016/j.regpep.2007.10.001http://dx.doi.org/10.1093/eurheartj/ehr309http://dx.doi.org/10.1093/eurheartj/ehr309http://dx.doi.org/10.1016/S0140-6736(06)69705-5http://dx.doi.org/10.1016/S1357-2725(03)00262-0http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
50. Busek P, Sedo A. Dipeptidyl peptidase-IV and related
proteases in braintumors. In: Lichtor T, editor. Evolution of
theMolecular biology of Brain Tumorsand the Therapeutic
Implications. InTech (2013). p. 235–69. doi:10.5772/53888
51. Yu DM, Yao T-W, Chowdhury S, Nadvi NA, Osborne B, Church WB,
et al.The dipeptidyl peptidase IV family in cancer and cell
biology. FEBS J (2010)277:1126–44.
doi:10.1111/j.1742-4658.2009.07526.x
52. Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R,
et al. Dipep-tidyl peptidase 4 is a functional receptor for the
emerging human coronavirus-EMC. Nature (2013) 495:251–4.
doi:10.1038/nature12005
53. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA,
Jarolim P,et al. Heart failure, saxagliptin and diabetes mellitus:
observations from theSAVOR – TIMI 53 randomized trial. Circulation
(2014) 130:1579–88. doi:10.1161/CIRCULATIONAHA.114.010389
54. Fadini GP, Avogaro A. Cardiovascular effects of DPP-4
inhibition: beyondGLP-1. Vascul Pharmacol (2011) 55:10–6.
doi:10.1016/j.vph.2011.05.001
55. Theiss HD, Brenner C, Engelmann MG, Zaruba M-M, Huber B,
Henschel V,et al. Safety and efficacy of SITAgliptin plus
GRanulocyte-colony-stimulatingfactor in patients suffering from
acute myocardial infarction (SITAGRAMI-trial) – rationale, design
and first interim analysis. Int J Cardiol (2010)145:282–4.
doi:10.1016/j.ijcard.2009.09.555
56. Theiss HD, Gross L, Vallaster M, David R, Brunner S, Brenner
C, et al. Antidi-abetic gliptins in combination with G-CSF enhances
myocardial function andsurvival after acute myocardial infarction.
Int J Cardiol (2013)
168:3359–69.doi:10.1016/j.ijcard.2013.04.121
57. Collins PJ, McMahon G, O’Brien P, O’Connor B. Purification,
identificationand characterisation of seprase from bovine serum.
Int J Biochem Cell Biol(2004) 36:2320–33.
doi:10.1016/j.biocel.2004.05.006
58. Lee KN, Jackson KW, Christiansen VJ, Lee CS, Chun J-G, McKee
PA.Antiplasmin-cleaving enzyme is a soluble form of fibroblast
activation protein.Blood (2006) 107:1397–404.
doi:10.1182/blood-2005-08-3452
59. Keane FM, Nadvi NA, Yao T-W, Gorrell MD. Neuropeptide Y,
B-type natri-uretic peptide, substance P and peptide YY are novel
substrates of fibroblastactivation protein-α. FEBS J (2011)
278:1316–32. doi:10.1111/j.1742-4658.2011.08051.x
60. O’Brien P, O’Connor BF. Seprase: an overview of an important
matrix serineprotease. Biochim Biophys Acta (2008) 1784:1130–45.
doi:10.1016/j.bbapap.2008.01.006
61. Keane FM, Yao T-W, Seelk S, Gall MG, Chowdhury S, Poplawski
SE, et al.Quantitation of fibroblast activation protein
(FAP)-specific protease activity inmouse, baboon and human fluids
and organs. FEBS Open Bio (2013)
4:43–54.doi:10.1016/j.fob.2013.12.001
62. Sulda ML, Abbott CA, Hildebrandt M. DPIV/CD26 and FAP in
cancer: atale of contradictions. Adv Exp Med Biol (2006)
575:197–206. doi:10.1007/0-387-32824-6_21
63. Narra K, Mullins SR, Lee H-O, Strzemkowski-Brun B, Magalong
K, Chris-tiansen VJ, et al. Phase II trial of single agent
Val-boroPro (talabostat) inhibit-ing fibroblast activation protein
in patients with metastatic colorectal cancer.Cancer Biol Ther
(2007) 6:1691–9. doi:10.4161/cbt.6.11.4874
64. Eager RM, Cunningham CC, Senzer N, Richards DA, Raju RN,
Jones B, et al.Phase II trial of talabostat and docetaxel in
advanced non-small cell lungcancer. Clin Oncol (R Coll Radiol)
(2009) 21:464–72. doi:10.1016/j.clon.2009.04.007
65. Eager RM, Cunningham CC, Senzer NN, Stephenson J, Anthony
SP, O’DaySJ, et al. Phase II assessment of talabostat and cisplatin
in second-line stage IVmelanoma. BMC Cancer (2009) 9:263.
doi:10.1186/1471-2407-9-263
66. Bjelke JR, Christensen J, Nielsen PF, Branner S, Kanstrup
AB, Wagtmann N,et al. Dipeptidyl peptidases 8 and 9: specificity
and molecular characterizationcompared with dipeptidyl peptidase
IV. Biochem J (2006) 396:391–9. doi:10.1042/BJ20060079
67. Ajami K, Abbott CA, McCaughan GW, Gorrell MD. Dipeptidyl
peptidase 9has two forms, a broad tissue distribution, cytoplasmic
localization and DPIV-like peptidase activity. Biochim Biophys Acta
(2004) 1679:18–28. doi:10.1016/j.bbaexp.2004.03.010
68. Qi SY, Riviere PJ, Trojnar J, Junien J-L, Akinsanya KO.
Cloning and charac-terization of dipeptidyl peptidase 10, a new
member of an emerging subgroupof serine proteases. Biochem J (2003)
373:179–89. doi:10.1042/BJ20021914
69. Justa-SchuchD,Möller U, Geiss-Friedlander R. The amino
terminus extensionin the long dipeptidyl peptidase 9 isoform
contains a nuclear localization
signal targeting the active peptidase to the nucleus. Cell Mol
Life Sci (2014)71(18):3611–26. doi:10.1007/s00018-014-1591-6
70. Ajami K, Pitman MR, Wilson CH, Park J, Menz RI, Starr AE, et
al. Stromalcell-derived factors 1alpha and 1beta, inflammatory
protein-10 and interferon-inducible T cell chemo-attractant are
novel substrates of dipeptidyl peptidase8. FEBS Lett (2008)
582:819–25. doi:10.1016/j.febslet.2008.02.005
71. Lu C, Tilan JU, Everhart L, Czarnecka M, Soldin SJ, Mendu
DR, et al. Dipep-tidyl peptidases as survival factors in Ewing
sarcoma family of tumors: impli-cations for tumor biology and
therapy. J Biol Chem (2011)
286:27494–505.doi:10.1074/jbc.M111.224089
72. Wilson CH, Indarto D, Doucet A, Pogson LD, Pitman MR, Menz
RI, et al.Identifying natural substrates for dipeptidyl peptidase 8
(DP8) and DP9using terminal amine isotopic labelling of substrates,
TAILS, reveals in vivoroles in cellular homeostasis and energy
metabolism. J Biol Chem (2013)288:13936–49.
doi:10.1074/jbc.M112.445841
73. Geiss-Friedlander R, Parmentier N, Möller U, Urlaub H, Van
den Eynde BJ,Melchior F. The cytoplasmic peptidase DPP9 is
rate-limiting for degradationof proline-containing peptides. J Biol
Chem (2009) 284:27211–9. doi:10.1074/jbc.M109.041871
74. Gall MG, Chen Y, Vieira de Ribeiro AJ, Zhang H, Bailey CG,
Spielman DS,et al. Targeted inactivation of dipeptidyl peptidase 9
enzymatic activity causesmouse neonate lethality. PLoS One (2013)
8:e78378. doi:10.1371/journal.pone.0078378
75. Dubois V, Van Ginneken C, De Cock H, Lambeir A-M, Van der
Veken P,Augustyns K, et al. Enzyme activity and immunohistochemical
localizationof dipeptidyl peptidase 8 and 9 in male reproductive
tissues. J HistochemCytochem (2009) 57:531–41.
doi:10.1369/jhc.2009.952739
76. Zhu H, Zhou Z-M, Lu L, Xu M, Wang H, Li J-M, et al.
Expression ofa novel dipeptidyl peptidase 8 (DPP8) transcript
variant, DPP8-v3, inhuman testis. Asian J Androl (2005) 7:245–55.
doi:10.1111/j.1745-7262.2005.00054.x
77. Pilla E, Möller U, Sauer G, Mattiroli F, Melchior F,
Geiss-Friedlander R. Anovel SUMO1-specific interacting motif in
dipeptidyl peptidase 9 (DPP9)that is important for enzymatic
regulation. J Biol Chem (2012)
287:44320–9.doi:10.1074/jbc.M112.397224
78. Pilla E, Kilisch M, Lenz C, Urlaub H, Geiss-Friedlander R.
The SUMO1-E67interacting loop peptide is an allosteric inhibitor of
the dipeptidyl peptidases8 and 9. J Biol Chem (2013) 288:32787–96.
doi:10.1074/jbc.M113.489179
79. Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele
MP, et al.Genome-wide association study identifies multiple
susceptibility loci for pul-monary fibrosis. Nat Genet (2013)
45:613–20. doi:10.1038/ng.2609
80. Yu DM, Wang XM, McCaughan GW, Gorrell MD. Extraenzymatic
functionsof the dipeptidyl peptidase IV-related proteins DP8 and
DP9 in cell adhe-sion, migration and apoptosis. FEBS J (2006)
273:2447–60. doi:10.1111/j.1742-4658.2006.05253.x
81. Yao TW, Kim WS, Yu DM, Sharbeen G, McCaughan GW, Choi KY, et
al. Anovel role of dipeptidyl peptidase 9 in epidermal growth
factor signaling. MolCancer Res (2011) 9:948–59.
doi:10.1158/1541-7786.MCR-10-0272
82. Matheeussen V, Waumans Y, Martinet W, Van Goethem S, Van der
Veken P,Scharpé S, et al. Dipeptidyl peptidases in atherosclerosis:
expression and role inmacrophage differentiation, activation and
apoptosis. Basic Res Cardiol (2013)108:350–64.
doi:10.1007/s00395-013-0350-4
83. Spagnuolo PA, Hurren R, Gronda M, MacLean N, Datti A,
Basheer A, et al.Inhibition of intracellular dipeptidyl peptidases
8 and 9 enhances partheno-lide’s anti-leukemic activity. Leukemia
(2013) 27:1236–44. doi:10.1038/leu.2013.9
84. Maes M, Lambeir A, Gilany K, Senten K, Van der Veken P,
Leiting B, et al.Kinetic investigation of human dipeptidyl
peptidase II (DPPII)-mediatedhydrolysis of dipeptide derivatives
and its identification as quiescent cellproline dipeptidase
(QPP)/dipeptidyl peptidase 7 (DPP7). Biochem J
(2005)324:315–24.
85. Kehoe K, Verkerk R, Sim Y, Waumans Y, Van der Veken P,
Lambeir A-M, et al.Validation of a specific prolylcarboxypeptidase
activity assay and its suitabilityfor plasma and serum
measurements. Anal Biochem (2013) 443:232–9.
doi:10.1016/j.ab.2013.09.002
86. O’Donoghue AJ, Eroy-Reveles AA, Knudsen GM, Ingram J, Zhou
M, Stat-nekov JB, et al. Global identification of peptidase
specificity by multiplexsubstrate profiling. Nat Methods (2012)
9:1095–100. doi:10.1038/nmeth.2182
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 38713
http://dx.doi.org/10.5772/53888http://dx.doi.org/10.1111/j.1742-4658.2009.07526.xhttp://dx.doi.org/10.1038/nature12005http://dx.doi.org/10.1161/CIRCULATIONAHA.114.010389http://dx.doi.org/10.1161/CIRCULATIONAHA.114.010389http://dx.doi.org/10.1016/j.vph.2011.05.001http://dx.doi.org/10.1016/j.ijcard.2009.09.555http://dx.doi.org/10.1016/j.ijcard.2013.04.121http://dx.doi.org/10.1016/j.biocel.2004.05.006http://dx.doi.org/10.1182/blood-2005-08-3452http://dx.doi.org/10.1111/j.1742-4658.2011.08051.xhttp://dx.doi.org/10.1111/j.1742-4658.2011.08051.xhttp://dx.doi.org/10.1016/j.bbapap.2008.01.006http://dx.doi.org/10.1016/j.bbapap.2008.01.006http://dx.doi.org/10.1016/j.fob.2013.12.001http://dx.doi.org/10.1007/0-387-32824-6_21http://dx.doi.org/10.1007/0-387-32824-6_21http://dx.doi.org/10.4161/cbt.6.11.4874http://dx.doi.org/10.1016/j.clon.2009.04.007http://dx.doi.org/10.1016/j.clon.2009.04.007http://dx.doi.org/10.1186/1471-2407-9-263http://dx.doi.org/10.1042/BJ20060079http://dx.doi.org/10.1042/BJ20060079http://dx.doi.org/10.1016/j.bbaexp.2004.03.010http://dx.doi.org/10.1016/j.bbaexp.2004.03.010http://dx.doi.org/10.1042/BJ20021914http://dx.doi.org/10.1007/s00018-014-1591-6http://dx.doi.org/10.1016/j.febslet.2008.02.005http://dx.doi.org/10.1074/jbc.M111.224089http://dx.doi.org/10.1074/jbc.M112.445841http://dx.doi.org/10.1074/jbc.M109.041871http://dx.doi.org/10.1074/jbc.M109.041871http://dx.doi.org/10.1371/journal.pone.0078378http://dx.doi.org/10.1371/journal.pone.0078378http://dx.doi.org/10.1369/jhc.2009.952739http://dx.doi.org/10.1111/j.1745-7262.2005.00054.xhttp://dx.doi.org/10.1111/j.1745-7262.2005.00054.xhttp://dx.doi.org/10.1074/jbc.M112.397224http://dx.doi.org/10.1074/jbc.M113.489179http://dx.doi.org/10.1038/ng.2609http://dx.doi.org/10.1111/j.1742-4658.2006.05253.xhttp://dx.doi.org/10.1111/j.1742-4658.2006.05253.xhttp://dx.doi.org/10.1158/1541-7786.MCR-10-0272http://dx.doi.org/10.1007/s00395-013-0350-4http://dx.doi.org/10.1038/leu.2013.9http://dx.doi.org/10.1038/leu.2013.9http://dx.doi.org/10.1016/j.ab.2013.09.002http://dx.doi.org/10.1016/j.ab.2013.09.002http://dx.doi.org/10.1038/nmeth.2182http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
87. Shariat-Madar Z, Mahdi F, Schmaier AH. Recombinant
prolylcarboxypepti-dase activates plasma prekallikrein. Blood
(2004) 103:4554–61. doi:10.1182/blood-2003-07-2510
88. Odya CE, Marinkovic DV, Hammon KJ, Stewart TA, Erdös EG.
Purificationand properties of prolylcarboxypeptidase
(angiotensinase C) from humankidney. J Biol Chem (1978)
253:5927–31.
89. Diano S. New aspects of melanocortin signaling: a role for
PRCP in α-MSH degradation. Front Neuroendocrinol (2011) 32:70–83.
doi:10.1016/j.yfrne.2010.09.001
90. Xu S, Lind L, Zhao L, Lindahl B, Venge P. Plasma
prolylcarboxypeptidase(angiotensinase C) is increased in obesity
and diabetes mellitus and relatedto cardiovascular dysfunction.
Clin Chem (2012) 58:1110–5. doi:10.1373/clinchem.2011.179291
91. Kehoe K, Brouns R, Verkerk R, Engelborghs S, De Deyn PP,
Hendriks D,et al. Prolyl carboxypeptidase activity decline
correlates with severity andshort-term outcome in acute ischemic
stroke. Neurochem Res (2015)
40:81–8.doi:10.1007/s11064-014-1468-y
92. Chiravuri M, Schmitz T, Yardley K, Underwood R, Dayal Y,
Huber BT. A novelapoptotic pathway in quiescent lymphocytes
identified by inhibition of a post-proline cleaving
aminodipeptidase: a candidate target protease, quiescent
cellproline dipeptidase. J Immunol (1999) 163:3092–9.
93. Mele DA, Bista P, Baez DV, Huber BT. Dipeptidyl peptidase 2
is an essentialsurvival factor in the regulation of cell
quiescence.Cell Cycle (2009) 8:2425–34.doi:10.4161/cc.8.15.9144
94. Danilov AV, Danilova OV, Brown JR, Rabinowitz A, Klein AK,
Huber BT.Dipeptidyl peptidase 2 apoptosis assay determines the
B-cell activation stageand predicts prognosis in chronic
lymphocytic leukemia. Exp Hematol (2010)38:1167–77.
doi:10.1016/j.exphem.2010.08.008
95. Maes M, Lambeir A, Van Der Veken P, De Winter B, Augustyns
K, Scharp S.In vivo effects of a potent, selective DPPII inhibitor:
UAMC00039 is a possibletool for the elucidation of the
physiological function of DPPII. Adv Exp MedBiol (2006) 575:73–85.
doi:10.1007/0-387-32824-6_8
96. Schulz I, Zeitschel U, Rudolph T, Ruiz-Carrillo D, Rahfeld
J-U, Gerhartz B,et al. Subcellular localization suggests novel
functions for prolyl endopeptidasein protein secretion. J Neurochem
(2005) 94:970–9. doi:10.1111/j.1471-4159.2005.03237.x
97. Dresdner K, Barker LA, Orlowski M, Wilk S. Subcellular
distribution of prolylendopeptidase and cation-sensitive neutral
endopeptidase in rabbit brain.J Neurochem (1982) 38:1151–4.
doi:10.1111/j.1471-4159.1982.tb05362.x
98. Moreno-Baylach MJ, Felipo V, Männistö PT, García-Horsman JA.
Expressionand traffic of cellular prolyl oligopeptidase are
regulated during cerebel-lar granule cell differentiation,
maturation, and aging. Neuroscience (2008)156:580–5.
doi:10.1016/j.neuroscience.2008.06.072
99. Myöhänen TT, Venäläinen JI, García-Horsman JA, Piltonen M,
MännistöPT. Distribution of prolyl oligopeptidase in the mouse
whole-body sectionsand peripheral tissues.Histochem Cell Biol
(2008) 130:993–1003. doi:10.1007/s00418-008-0468-x
100. Walter R. Partial purification and characterization of
post-proline cleavingenzyme: enzymatic inactivation of
neurohypophyseal hormones by kidneypreparations of various species.
Biochim Biophys Acta (1976)
422:138–58.doi:10.1016/0005-2744(76)90015-2
101. Kato T, Nakano T, Kojima K, Nagatsu T, Sakakibara S.
Changes in prolylendopeptidase duringmaturation of rat brain and
hydrolysis of substance P bythe purified enzyme. J Neurochem (1980)
35:527–35. doi:10.1111/j.1471-4159.1980.tb03687.x
102. Moriyama A, Nakanishi M, Sasaki M. Porcine muscle prolyl
endopeptidaseand its endogenous substrates. J Biochem (1988)
104:112–7.
103. Schönlein C, Heins J, Barth A. Purification and
characterization of prolylendopeptidase from pig brain. Biol Chem
Hoppe Seyler (1990)
371:1159–64.doi:10.1515/bchm3.1990.371.2.1159
104. Kusuhara M, Hachisuka H, Nakano S, Sasai Y. Purification
and characteriza-tion of prolyl endopeptidase from rat skin. J
Dermatol Sci (1993) 6:138–45.doi:10.1016/0923-1811(93)90004-9
105. Bellemère G, Morain P, Vaudry H, Jégou S. Effect of S
17092, a novel prolylendopeptidase inhibitor, on substance P and
alpha-melanocyte-stimulatinghormone breakdown in the rat brain. J
Neurochem (2003) 84:919–29.
doi:10.1046/j.1471-4159.2003.01536.x
106. Browne P, O’Cuinn G. An evaluation of the role of a
pyroglutamyl peptidase, apost-proline cleaving enzyme and a
post-proline dipeptidyl amino peptidase,
each purified from the soluble fraction of guinea-pig brain, in
the degrada-tion of thyroliberin in vitro. Eur J Biochem (1983)
137:75–87. doi:10.1111/j.1432-1033.1983.tb07798.x
107. Männisto PT, Venäläinen J, Jalkanen A, García-Horsman JA.
Prolyl oligopep-tidase: a potential target for the treatment of
cognitive disorders. Drug NewsPerspect (2007) 20:293–305.
doi:10.1358/dnp.2007.20.5.1120216
108. García-Horsman JA, Männistö PT, Venäläinen JI. On the role
of prolyloligopeptidase in health and disease. Neuropeptides (2007)
41:1–24. doi:10.1016/j.npep.2006.10.004
109. Camargo AC, Caldo H, Emson PC. Degradation of neurotensin
byrabbit brain endo-oligopeptidase A and endo-oligopeptidase B
(proline-endopeptidase). Biochem Biophys Res Commun (1983)
116:1151–9. doi:10.1016/S0006-291X(83)80263-0
110. Cunningham DF, O’Connor B. Proline specific peptidases.
Biochim BiophysActa (1997) 1343:160–86.
doi:10.1016/S0167-4838(97)00134-9
111. Greene LJ, Spadaro AC, Martins AR, Perussi De Jesus WD,
Camargo AC.Brain endo-oligopeptidase B: a post-proline cleaving
enzyme that inactivatesangiotensin I and II. Hypertension (1982)
4:178–84. doi:10.1161/01.HYP.4.2.178
112. Griffiths EC, McDermott JR, Smith AI. Inactivation of
thyrotropin-releasinghormone (TRH) and (3Me-His) TRH by brain
peptidases studied by high-performance liquid chromatography.
Neurosci Lett (1982) 28:61–5. doi:10.1016/0304-3940(82)90209-9
113. Mendez M, Cruz C, Joseph-Bravo P, Wilk S, Charli JL.
Evaluation of therole of prolyl endopeptidase and pyroglutamyl
peptidase I in the metabolismof LHRH and TRH in brain.
Neuropeptides (1990) 17:55–62. doi:10.1016/0143-4179(90)90050-9
114. Mentlein R, von Kolszynski M, Sprang R, Lucius R.
Proline-specific proteasesin cultivated neuronal and glial cells.
Brain Res (1990) 527:159–62. doi:10.1016/0006-8993(90)91076-S
115. Toide K, Okamiya K, Iwamoto Y, Kato T. Effect of a novel
prolyl endopepti-dase inhibitor, JTP-4819, on prolyl endopeptidase
activity and substance P-and arginine-vasopressin-like
immunoreactivity in the brains of aged rats.J Neurochem (1995)
65:234–40. doi:10.1046/j.1471-4159.1995.65010234.x
116. O’Reilly PJ, Hardison MT, Jackson PL, Xu X, Snelgrove RJ,
Gaggar A, et al.Neutrophils contain prolyl endopeptidase and
generate the chemotactic pep-tide, PGP, from collagen. J
Neuroimmunol (2009) 217:51–4.
doi:10.1016/j.jneuroim.2009.09.020
117. Cavasin MA, Rhaleb N-E, Yang X-P, Carretero OA. Prolyl
oligopeptidase isinvolved in release of the antifibrotic peptide
Ac-SDKP. Hypertension (2004)43:1140–5.
doi:10.1161/01.HYP.0000126172.01673.84
118. Tenorio-Laranga J, Peltonen I, Keskitalo S, Duran-Torres G,
Natarajan R,Männistö PT, et al. Alteration of prolyl oligopeptidase
and activated α-2-macroglobulin in multiple sclerosis subtypes and
in the clinically isolatedsyndrome. Biochem Pharmacol (2013)
85:1783–94. doi:10.1016/j.bcp.2013.04.018
119. Tenorio-Laranga J, Coret-Ferrer F, Casanova-Estruch B,
Burgal M, García-Horsman JA. Prolyl oligopeptidase is inhibited in
relapsing-remitting multiplesclerosis. J Neuroinflammation (2010)
7:23. doi:10.1186/1742-2094-7-23
120. Yoshimoto T, Kado K, Matsubara F, Koriyama N, Kaneto H,
Tsura D. Specificinhibitors for prolyl endopeptidase and their
anti-amnesic effect. J Pharmaco-biodyn (1987) 10:730–5.
doi:10.1248/bpb1978.10.730
121. Toide K, Iwamoto Y, Fujiwara T, Abe H. JTP-4819: a novel
prolyl endopep-tidase inhibitor with potential as a cognitive
enhancer. J Pharmacol Exp Ther(1995) 274:1370–8.
122. Shinoda M, Matsuo A, Toide K. Pharmacological studies of a
novelprolyl endopeptidase inhibitor, JTP-4819, in rats with middle
cerebral arteryocclusion. Eur J Pharmacol (1996) 305:31–8.
doi:10.1016/0014-2999(96)00173-2
123. Shishido Y, Furushiro M, Tanabe S, Shibata S, Hashimoto S,
Yokokura T.Effects of prolyl endopeptidase inhibitors and
neuropeptides on delayedneuronal death in rats. Eur J Pharmacol
(1999) 372:135–42. doi:10.1016/S0014-2999(99)00185-5
124. Katsube N, Sunaga K, Aishita H, Chuang DM, Ishitani R.
ONO-1603, a poten-tial antidementia drug, delays age-induced
apoptosis and suppresses over-expression of
glyceraldehyde-3-phosphate dehydrogenase in cultured centralnervous
system neurons. J Pharmacol Exp Ther (1999) 288:6–13.
125. D’Agostino G, Kim JD, Liu Z-W, Jeong JK, Suyama S,
Calignano A, et al. Prolylendopeptidase-deficient mice have reduced
synaptic spine density in the CA1
Frontiers in Immunology | www.frontiersin.org August 2015 |
Volume 6 | Article 38714
http://dx.doi.org/10.1182/blood-2003-07-2510http://dx.doi.org/10.1182/blood-2003-07-2510http://dx.doi.org/10.1016/j.yfrne.2010.09.001http://dx.doi.org/10.1016/j.yfrne.2010.09.001http://dx.doi.org/10.1373/clinchem.2011.179291http://dx.doi.org/10.1373/clinchem.2011.179291http://dx.doi.org/10.1007/s11064-014-1468-yhttp://dx.doi.org/10.4161/cc.8.15.9144http://dx.doi.org/10.1016/j.exphem.2010.08.008http://dx.doi.org/10.1007/0-387-32824-6_8http://dx.doi.org/10.1111/j.1471-4159.2005.03237.xhttp://dx.doi.org/10.1111/j.1471-4159.2005.03237.xhttp://dx.doi.org/10.1111/j.1471-4159.1982.tb05362.xhttp://dx.doi.org/10.1016/j.neuroscience.2008.06.072http://dx.doi.org/10.1007/s00418-008-0468-xhttp://dx.doi.org/10.1007/s00418-008-0468-xhttp://dx.doi.org/10.1016/0005-2744(76)90015-2http://dx.doi.org/10.1111/j.1471-4159.1980.tb03687.xhttp://dx.doi.org/10.1111/j.1471-4159.1980.tb03687.xhttp://dx.doi.org/10.1515/bchm3.1990.371.2.1159http://dx.doi.org/10.1016/0923-1811(93)90004-9http://dx.doi.org/10.1046/j.1471-4159.2003.01536.xhttp://dx.doi.org/10.1046/j.1471-4159.2003.01536.xhttp://dx.doi.org/10.1111/j.1432-1033.1983.tb07798.xhttp://dx.doi.org/10.1111/j.1432-1033.1983.tb07798.xhttp://dx.doi.org/10.1358/dnp.2007.20.5.1120216http://dx.doi.org/10.1016/j.npep.2006.10.004http://dx.doi.org/10.1016/j.npep.2006.10.004http://dx.doi.org/10.1016/S0006-291X(83)80263-0http://dx.doi.org/10.1016/S0006-291X(83)80263-0http://dx.doi.org/10.1016/S0167-4838(97)00134-9http://dx.doi.org/10.1161/01.HYP.4.2.178http://dx.doi.org/10.1161/01.HYP.4.2.178http://dx.doi.org/10.1016/0304-3940(82)90209-9http://dx.doi.org/10.1016/0304-3940(82)90209-9http://dx.doi.org/10.1016/0143-4179(90)90050-9http://dx.doi.org/10.1016/0143-4179(90)90050-9http://dx.doi.org/10.1016/0006-8993(90)91076-Shttp://dx.doi.org/10.1016/0006-8993(90)91076-Shttp://dx.doi.org/10.1046/j.1471-4159.1995.65010234.xhttp://dx.doi.org/10.1016/j.jneuroim.2009.09.020http://dx.doi.org/10.1016/j.jneuroim.2009.09.020http://dx.doi.org/10.1161/01.HYP.0000126172.01673.84http://dx.doi.org/10.1016/j.bcp.2013.04.018http://dx.doi.org/10.1016/j.bcp.2013.04.018http://dx.doi.org/10.1186/1742-2094-7-23http://dx.doi.org/10.1248/bpb1978.10.730http://dx.doi.org/10.1016/0014-2999(96)00173-2http://dx.doi.org/10.1016/0014-2999(96)00173-2http://dx.doi.org/10.1016/S0014-2999(99)00185-5http://dx.doi.org/10.1016/S0014-2999(99)00185-5http://www.frontiersin.org/Immunology/http://www.frontiersin.orghttp://www.frontiersin.org/Immunology/archive
-
Waumans et al. The DPP family, PREP and PRCP in immunity and
inflammation
region of the hippocampus, impaired LTP, and spatial learning
and memory.Cereb Cortex (2013) 23:2007–14.
doi:10.1093/cercor/bhs199
126. Di Daniel E, Glover CP, Grot E, Chan MK, Sanderson TH,
White JH,et al. Prolyl oligopeptidase binds to GAP-43 and functions
without its pep-tidase activity. Mol Cell Neurosci (2009)
41:373–82. doi:10.1016/j.mcn.2009.03.003
127. Szeltner Z, Morawski M, Juhász T, Szamosi I, Liliom K,
Csizmók V, et al.GAP43 shows partial co-localisation but no strong
physical interaction withprolyl oligopeptidase. Biochim Biophys
Acta (2010) 1804:2162–76. doi:10.1016/j.bbapap.2010.09.010
128. Matsuda T, Sakaguchi M, Tanaka S, Yoshimoto T, Takaoka M.
Prolyl oligopep-tidase is a glyceraldehyde-3-phosphate
dehydrogenase-binding protein thatregulates genotoxic
stress-induced cell death. Int J Biochem Cell Biol (2013)45:850–7.
doi:10.1016/j.biocel.2013.01.009
129. Lambeir A-M. Interaction of prolyl oligopeptidase with
α-synuclein.CNS Neurol Disord Drug Targets (2011) 10:349–54.
doi:10.2174/187152711794653878
130. Hannula M, Myöhänen TT, Tenorio-Laranga J, Männistö PT,
Garcia-Horsman JA. Prolyl oligopeptidase colocalizes with
α-synuclein, β-amyloid,tau protein and astroglia in the post-mortem
brain samples with Parkin-son’s and Alzheimer’s diseases.
Neuroscience (2013) 242:140–50.
doi:10.1016/j.neuroscience.2013.03.049
131. Brandt I, Gérard M, Sergeant K, Devreese B, Baekelandt V,
Augustyns K, et al.Prolyl oligopeptidase stimulates the aggregation
of alpha-synuclein. Peptides(2008) 29:1472–8.
doi:10.1016/j.peptides.2008.05.005
132. Dimitrijević M, Stanojević S, Mitić K, Kustrimović N, Vujić
V, Miletić T, et al.The anti-inflammatory effect of neuropeptide Y
(NPY) in rats is dependenton dipeptidyl peptidase 4 (DP4) activity
and age. Peptides (2008)
29:2179–87.doi:10.1016/j.peptides.2008.08.017
133. Wang Z, Grigo C, Steinbeck J, von Hörsten S, Amann K,
Daniel C. SolubleDPP4 originates in part from bone marrow cells and
not from the kidney.Peptides (2014) 57:109–17.
doi:10.1016/j.peptides.2014.05.006
134. Olivo RD, Teixeira Cde F, Silveira PF. Representative
aminopeptidases andprolyl endopeptidase from murine macrophages:
comparative activity levelsin resident and elicited cells. Biochem
Pharmacol (2005) 69:1441–50. doi:10.1016/j.bcp.2005.03.002
135. Zhong J, Rao X, Deiuliis J, Braunstein Z, Narula V, Hazey
J, et al. A poten-tial role for dendritic
cell/macrophage-expressing DPP4 in obesity-inducedvisceral
inflammation. Diabetes (2013) 62:149–57. doi:10.2337/db12-0230
136. Maes M-B, Dubois V, Brandt I, Lambeir A-M, Van der Veken P,
Augustyns K,et al. Dipeptidyl peptidase 8/9-like activity in human
leukocytes. J Leukoc Biol(2007) 81:1252–7.
doi:10.1189/jlb.0906546
137. Bauvois B, Sancéau J, Wietzerbin J. Human U937 cell surface
peptidase activ-ities: characterization and degradative effect on
tumor necrosis factor-alpha.Eur J Immunol (1992) 22:923–30.
doi:10.1002/eji.1830220407